The long-term goal of the proposed research is to understand the molecular genetic mechanisms underlying craniofacial development. Craniofacial malformations, including cleft palate, occur with a frequency of 1 in 600 live births in the United States. Despite the prevalence of cleft palate in the human population, the pathogenic processes that lead to cleft palate are not well understood. Mice with mutations that cause cleft palate provide excellent animal models to determine the molecular mechanisms underlying normal palate development and cleft palate formation. A targeted mutation in the mouse Jag2 gene causes complete penetrance of cleft palate. Jag2 encodes a cell surface ligand for the Notch family receptors and is expressed throughout the oral epithelium during palate development. This proposal addresses the following questions: (1) what specific cellular and molecular processes during palate development depend on Jag2 function? (2) which Notch receptor(s) mediates Jag2 function in palate development? (3) what molecules act in the Jag2-Notch signaling pathway to regulate palate development? A combination of molecular, genetic, and embryological approaches will be used to find answers to these questions. These studies will provide insights into molecular and cellular mechanisms governing palate development and will greatly extend current understanding of the mammalian Notch signaling pathway.